Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA Trial.

PURPOSE To determine whether (1) immunohistochemical (IHC) HER2 status (ie, 2+ or 3+), (2) degree of fluorescence in situ hybridization (FISH) amplification according to (2a) HER2/CEP17 ratio or (2b) HER2 gene copy number, or (3) polysomy significantly influenced clinical outcome for patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer enrolled in the Herceptin Adjuvant trial of trastuzumab versus no trastuzumab administered after completion of chemotherapy. PATIENTS AND METHODS IHC and/or FISH analyses were performed locally and required central confirmation as indicating HER2 positivity for trial entry. FISH data from the central HER2 analysis on patients in the 1-year trastuzumab and no trastuzumab arms were assessed in relation to disease-free survival (DFS) after a median 2 years of follow-up. RESULTS Central FISH results were available for 2,071 (61%) of the 3,401 patients randomized to the 2 arms. Among patients with FISH-positive disease, (1) the hazard ratios for trastuzumab versus no trastuzumab were 0.56 (95% CI, 0.32 to 0.99) for locally IHC2+ cases (n = 340) and 0.80 (95% CI, 0.40 to 1.61) for centrally IHC2+ cases (n = 299). There was no significant prognostic relationship between (2a) HER2 FISH ratio, (2b) HER2 copy number, or (3) polysomy and DFS in the control arm or predictive relationship defining differential benefit from trastuzumab. CONCLUSION There was no evidence for reduced benefit of trastuzumab in HER2 IHC2+FISH+ cases. The degree of HER2 amplification does not influence prognosis or benefit from adjuvant trastuzumab in patients treated with prior adjuvant chemotherapy.

[1]  Jorma Isola,et al.  Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. , 2006, The New England journal of medicine.

[2]  E. Perez,et al.  Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer , 2007 .

[3]  Jorma Isola,et al.  Topoisomerase IIalpha gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  S. Paik,et al.  HER2 status and benefit from adjuvant trastuzumab in breast cancer. , 2008, The New England journal of medicine.

[5]  I. Ellis,et al.  Human epidermal growth factor receptor 2 status correlates with lymph node involvement in patients with estrogen receptor (ER) negative, but with grade in those with ER-positive early-stage breast cancer suitable for cytotoxic chemotherapy. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[7]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.

[8]  R. Gelber,et al.  Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[9]  Alan Mackay,et al.  Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines , 2008, Laboratory Investigation.

[10]  John R. Mackey,et al.  Phase III Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Docetaxel (AC→T) with Doxorubicin and Cyclophosphamide Followed by Docetaxel and Trastuzumab (AC→TH) with Docetaxel, Carboplatin and Trastuzumab (TCH) in Her2neu Positive Early Breast Cancer Patients: BCIRG 006 Study. , 2009 .

[11]  D. Larsimont,et al.  HER-2 amplification and topoisomerase IIalpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[12]  T. Grogan,et al.  The Influence of Polysomy 17 on HER2 Gene and Protein Expression in Adenocarcinoma of the Breast: A Fluorescent In Situ Hybridization, Immunohistochemical, and Isotopic mRNA In Situ Hybridization Study , 2005, The American journal of surgical pathology.

[13]  Greg Yothers,et al.  Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. , 2005, The New England journal of medicine.

[14]  E. Perez,et al.  Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  S. Paik,et al.  Benefit from adjuvant trastuzumab may not be confined to patients with IHC 3+ and/or FISH-positive tumors: Central testing results from NSABP B-31 , 2007 .

[16]  David Cameron,et al.  2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial , 2007, The Lancet.

[17]  Anthony Rhodes,et al.  American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. , 2006, Archives of pathology & laboratory medicine.

[18]  W Godolphin,et al.  Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. , 1989, Science.

[19]  M. Dowsett,et al.  Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. , 2005, The New England journal of medicine.

[20]  T. Yamamoto,et al.  The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity. , 1986, Science.

[21]  Patrick Neven,et al.  Polysomy 17 in breast cancer: clinicopathologic significance and impact on HER-2 testing. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  M. Dowsett,et al.  Standardization of HER2 testing: results of an international proficiency-testing ring study , 2007, Modern Pathology.

[23]  M. Greenwood A Report on the Natural Duration of Cancer. , 1926 .

[24]  Gottfried Konecny,et al.  Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. , 2003, Journal of the National Cancer Institute.